SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment (CICI) are major side effects of cancer treatment that frequently persist long into survivorship. No drugs have been approved by the US Food and Drug Administration to prevent and/or adequately manage CIPN and CICI. This application aims at filling this void. A concern when designing drugs to manage CIPN and CICI is that they should not impair tumor control. Ideally, agents to control these neurotoxicities should also enhance tumor control. Recent findings indicate that inhibitors of histone deacetylase 6 (HDAC6) meet these goals. HDAC6 de-acetylates non-histone cytosolic proteins like tubulin without inducing epigenetic changes. Recent preclinical and clinical data show promise for HDAC6 inhibitors to improve tumor control. We recently showed that HDAC6 inhibition fully reverses established CIPN in cisplatin-treated mice. This was associated with restoration of mitochondrial health in sensory neurons. Preliminary data indicate that co- administration of HDAC6 inhibitors protect against CIPN by preventing mitochondrial damage. Additional preliminary data indicate that HDAC6 inhibition also reverses established CICI and associated brain mitochondrial damage. Our hypothesis is that HDAC6 inhibition prevents and reverses CIPN and CICI in mice with or without tumors by targeting mitochondrial health, oxidative stress, and downstream neuroimmune pathways. We will test our hypothesis in 3 specific aims: Aim1: Determine the capacity of HDAC6 inhibitors to prevent CIPN in mice with or without tumors. Aim 2: Determine the effect of HDAC6 inhibition on established CIPN. Aim 3: Determine whether the beneficial effects of HDAC6 inhibition extend to CICI. In aims 1 and 3, we will investigate the effect of HDAC6 inhibitors on tumor control and ensure that HDAC6 inhibitors also prevent CIPN and CICI in the presence of a tumor. This study is innovative because we propose to target HDAC6 activity in neurons to control neurotoxicities while at the same time enhancing cancer control. The expected outcome is significant because it will identify HDAC6 inhibition as a realistic novel approach to control CIPN and CICI. This will increase the quality of life of millions of cancer patients and survivors. Clinical trials to examine the effect of HDAC6 inhibitors on tumor control are already underway, and therefore the expected results of this project should rapidly convince clinicians to examine the value of HDAC6 inhibitors for management of both CIPN and CICI. Identification of HDAC6 inhibitors as drugs that can be used after completion of chemotherapy to completely resolve established CIPN and CICI will be of great benefit for cancer survivors suffering every day from these persistent neurotoxicities.